TUB-010, a novel anti-CD30 antibody-drug conjugate based on Tub-tag technology, widens the therapeutic window by reducing toxicity while maintaining high efficacy

Abstract

TUB-010 is a next-generation antibody-drug conjugate (ADC) targeting CD30, which is expressed on various hematopoietic malignancies such as Hodgkin lymphoma and anaplastic large cell lymphoma. Patients with refractory and relapsed CD30-positive cancers often lack effective and tolerable therapy options. Among the therapeutic options for these patients is brentuximab vedotin (Adcetris), a monomethyl auristatin E (MMAE)-delivering anti-CD30 ADC with a mean drug-to antibody ratio (DAR) of 4. Adcetris exhibits a high response rate at the cost of significant toxicities, among which neutropenia and peripheral neuropathy are the most prevalent adverse events, which are likely driven by the payload MMAE and instability of the maleimide conjugation chemistry. TUB-010 uses the same antibody brentuximab and payload MMAE as Adcetris, but instead of maleimide chemistry, TUB-010 is based on the Tub-tag conjugation strategy, which enables the generation of a homogenous and site-specific DAR 2 ADC with unique biophysical properties. This new technology stably attaches MMAE to the hydrophilic Tub-tag peptides on the light chains via chemoenzymatic conjugation using the enzyme tubulin tyrosine ligase. TUB-010 demonstrates similar binding affinity, internalization and lysosomal release characteristics as Adcetris in CD30-positive cells. When normalized to the MMAE concentration, TUB-010 shows comparable in vitro cytotoxic efficacy as well as similar bystander activity compared to Adcetris on established cancer cell lines. Importantly, TUB-010 exhibits higher stability with neglectable premature deconjugation in circulation and reduced high molecular weight species formation as well as lower non-specific cytotoxicity on target-negative cells compared to Adcetris. As a consequence, TUB-010 induces superior tumor control compared to Adcetris when dosed at equal MMAE concentrations in vivo and also shows lower toxicity and higher tolerability in rodents and non-human primates. Taken together, TUB-010 is a novel and potential best-in-class anti-CD30 ADC with improved biophysical properties designed to deliver the cytotoxic payload with higher precision and with a wider therapeutic window than Adcetris using Tub-tag conjugation technology. Therefore, TUB-010 may increase the clinical benefit of ADC therapies for patients with CD30-positive malignancies.